scholarly journals Distinct Modes of Ongoing Antigen Interactions Shape Intraclonal Dynamics in Splenic Marginal Zone Lymphoma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1330-1330
Author(s):  
Laura Zaragoza-Infante ◽  
Andreas Agathangelidis ◽  
Valentin Junet ◽  
Nikos Pechlivanis ◽  
Triantafylia Koletsa ◽  
...  
Keyword(s):  
High Throughput ◽  
Research Funding ◽  
Large Scale ◽  
Marginal Zone ◽  
Marginal Zone Lymphoma ◽  
The Other ◽  
Splenic Marginal Zone Lymphoma ◽  
Gene Repertoire ◽  
Graph Metrics ◽  
The Impact

Abstract Almost one-third of all splenic marginal zone lymphoma (SMZL) cases express B cell receptor immunoglobulin (BcR IG) encoded by the IGHV1-2*04 gene. Such cases display a distinctive profile of genomic aberrations (e.g. higher incidence of NOTCH2 and KLF2 mutations) and a more aggressive clinical course compared to SMZL cases utilizing other IGHV genes. Such skewing of the BcR IG gene repertoire implicates antigen selection in SMZL ontogeny. Although the supportive evidence is compelling, it mostly derives from low-throughput approaches, which are inherently limited in their capacity to capture the complexity of the BcR IG gene repertoire. This hinders the comprehensive assessment of the subclonal architecture of SMZL that could offer insight into the dynamics of antigen-IG interactions. Here, we sought to overcome this limitation through a high-throughput immunogenetic investigation of SMZL, focusing on the detailed characterization of somatic hypermutation (SHM) and intraclonal diversification (ID) profiles. Our study included 22 cases utilizing the IGHV1-2*04 gene and 36 cases utilizing other IGHV genes. IGHV-IGHD-IGHJ (IGH) gene rearrangements were PCR-amplified and libraries were sequenced on the Illumina MiSeq platform. Data was analyzed with the IMGT/HighV-QUEST and TRIP software as well as a novel bioinformatics/biostatistics pipeline. Clonotypes were defined as unique combinations of a given IGHV gene+VH CDR3 amino acid (aa) sequence. Only IGH gene rearrangement sequences assigned to the dominant clonotypes of each case were assessed. In detail, all nucleotide variants (nt vars, i.e. all sequences clustered in the same dominant clonotype yet displaying distinct SHM profiles) were identified and further analyzed. Starting from the most abundant nt var, a network was built representing its connections with all other nt vars. For this analysis, we introduce the terms 'most relevant pathway' (MRP) corresponding to the pathway including connected nt vars with the highest total number of IGH sequences; and 'longest mutational pathways' (LMP) corresponding to the pathways with the highest number of nt vars (Fig. 1). Different graph metrics assessed the impact of ID in different SMZL subgroups: the first one focuses on the 'most relevant pathway' and quantifies SHM convergence [ratio of the total number of IGH sequences corresponding to the nt vars of this pathway to the number of IGH sequences in the most abundant nt var]; while the second refers to the length of the 'longest mutational pathways'. Cases lacking additional connected nt vars [length of the LMP=1; 3 IGHV1-2*04 cases and 4 non-IGHV1-2*04 cases] were excluded. Consequently, the analysis included 19 IGHV1-2*04 cases and 32 non-IGHV1-2*04 cases. Significant differences were noted in the SHM and ID profiles between groups; the IGHV1-2*04 group had significantly (p<0.01) higher convergence values ranging from 0.009 to 1.243 (median: 0.102), as opposed to the non-IGHV1-2*04 group (range: 0.002-1.13, median: 0.014), overall suggesting that stronger selective pressures act in SMZL cases expressing the IGHV1-2*04 versus others. Moreover, IGHV1-2*04 cases displayed significantly (p<0.01) longer mutational pathways (length range: 2-6, median: 3) compared to the other group (range: 2-5, median: 2), alluding to more pronounced ID arising due to ongoing SHM. Finally, all mutations leading to aa changes were analyzed in the context of ID networks. More recurrent aa mutations were identified amongst cases with higher levels of convergence. For instance, the VH FR2 M39I change, one of the most prominent recurrent SHMs in the IGHV1-2*04 group, was found in the most abundant nt var in 13/19 IGHV1-2*04 cases, while it was identified in nt vars with extra mutations in another 3 cases. Of interest, it was present at the end of the mutational pathways in these 16 cases, whilst in the other group it was present only in one case using the IGHV1-2*02 gene, and absent in the rest (p<0.01). In conclusion, in the first large-scale high-throughput immunogenetic analysis of SMZL we provide strong evidence for more pronounced antigenic pressure in cases utilizing IGHV1-2*04 versus other IGHV genes. Our findings highlight a unique subclonal architecture for IGHV1-2*04 SMZL and corroborate the hypothesis that this group may represent a distinct molecular variant of SMZL. Figure 1 Figure 1. Disclosures Rossi: Abbvie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Verastem: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Cellestia: Honoraria, Research Funding. Chatzidimitriou: Janssen: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. Stamatopoulos: Janssen: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding.

Distinctive Patterns of Intraclonal Diversification In IGHV1-2*04 Immunoglobulin Receptors of Patients with Splenic Marginal Zone Lymphoma: A of Ongoing Interactions with Antigen?

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2638-2638
Author(s):  
Vasilis Bikos ◽  
Evangelia Stalika ◽  
Nikos Darzentas ◽  
Maria Karypidou ◽  
Panagiotis Baliakas ◽  
...  
Keyword(s):  
Amino Acid ◽  
Research Funding ◽  
Large Scale ◽  
Marginal Zone ◽  
Somatic Hypermutation ◽  
Marginal Zone Lymphoma ◽  
Splenic Marginal Zone Lymphoma ◽  
Antigen Binding Site ◽  
Molecular Features ◽  
Major Subset

Abstract Abstract 2638 We recently demonstrated that over 30% of cases with splenic marginal-zone lymphoma (SMZL) express distinctive immunoglobulin (IG) receptors that utilize a single polymorphic variant of the IGHV1-2 gene (IGHV1-2*04) and also exhibit restricted antigen-binding site motifs and precise targeting of somatic hypermutation (SHM). On these grounds, we proposed the existence of molecular subtypes of SMZL defined by immunogenetic analysis of the IG receptors with implications for selection by specific (super) antigenic element(s) in the development of at least a major subset of SMZL. In order to gain insight as to whether antigen involvement is relevant only prior to the malignant transformation or if it continues to affect the SMZL clone itself leading to intraclonal diversification (ID) through ongoing SHM, we conducted a large-scale subcloning study of rearranged IG heavy variable genes, in a total of 471 subcloned sequences from 22 SMZL cases. The analysis was intentionally biased towards cases expressing IGHV1-2*04 receptors that exhibit a series of distinctive immunogenetic features, including biased usage of the IGHD3-3 and IGHD3-10 genes, unusually long heavy complementarity-determining region 3 (VH CDR3) and minimally/borderline mutated status (identity to the germline in the range of 97–99.6%). Hence, the study group included 16 IGHV1-2*04 cases and 6 cases utilizing other IGHV genes. PCR reactions were run using the high-fidelity Accuprime Pfx polymerase and a median of 21 (9–46) colonies/case were analyzed. All “non-ubiquitous” sequence changes from the germline were evaluated and recorded as follows: (i) unconfirmed mutation (UCM) - a mutation observed in only one subcloned sequence from the same sample; (ii) confirmed mutation (CM) - a mutation observed in more than one but in less than all subcloned sequences from the same sample. Overall, 15/22 cases (68%) carried intraclonally diversified IGHV-D-J genes with CMs amongst subclones, of which 12 utilized the IGHV1-2*04 gene whereas the remaining 3 utilized other IGHV genes. The high frequency of ID within the IGHV1-2*04 group, ranging from limited to (often) pronounced, is noteworthy in view of the generally low level of SHM among IGHV1-2*04 receptors. Detailed analysis of the distribution and molecular features of CMs revealed: (i) restricted ID patterns, in the sense of identical mutations in certain VH positions among subclones of different cases; (ii) “hotspots” of ID, i.e. particular codons exhibiting intense ongoing mutational activity (especially notable in this respect was codon 39 in VH FR2); (iii) a predominance of conservative amino acid changes, characterized by somatically introduced amino acid belonging to the same biochemical category as the mutating amino acid; and (iv) limited diversification within VH CDR3. Additionally, in 7/12 IGHV1-2*04 cases with CMs, identified ID patterns delineate distinct “clusters” of subcloned sequences with unique as well as shared mutations and closely similar if not identical VH CDR3s (including identical VH CDR3 length), pointing to “branching” of the malignant clone into distinct subclones, perhaps able to evolve along related yet distinct pathways. In conclusion, our study indicates that the SHM mechanism may continuously operate in certain subsets of SMZL, especially those expressing IGHV1-2*04 receptors. Although the precise timing of interactions with antigen(s) and their functional implications for SMZL evolution will likely remain difficult to define accurately, the results reported here suggest a role for persistent antigenic stimulation, at least for certain immunogenetically defined subsets of SMZL. Disclosures: Mollejo: Red Temática de Investigación Cooperativa en Cancer (RETICC): Research Funding; Asociación Española contra el Cancer: Research Funding.

Over 30% of Patients with Splenic Marginal Zone Lymphoma Express Distinctive Antigen Receptors Utilizing a Single Immunoglogulin Variable Gene: Implications for the Origin and Selection of the Neoplastic Cells

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 634-634 ◽  
Author(s):  
Vasilis Bikos ◽  
Nikos Darzentas ◽  
Anastasia Hadzidimitriou ◽  
Zadie Davis ◽  
Sarah Hockley ◽  
...  
Keyword(s):  
Amino Acid ◽  
Marginal Zone ◽  
Marginal Zone Lymphoma ◽  
Single Amino Acid ◽  
Histopathological Diagnosis ◽  
Splenic Marginal Zone Lymphoma ◽  
Gene Repertoire ◽  
Single Amino Acid Change ◽  
Vh Domain ◽  
Selection Of

Abstract Abstract 634 We systematically explored the immunoglobulin (IG) gene repertoire in 337 cases with splenic marginal-zone lymphoma (SMZL), by far the largest series yet. To resolve classification uncertainties, we included in the analysis only cases with a diagnosis of SMZL based on spleen histopathological findings or cases fulfilling the 2008 SBLG criteria (Matutes et al. Leukemia 2008). We here report that the IG heavy variable (IGHV) gene repertoire in SMZL is remarkably biased, with only three genes accounting for 45.8% of cases (IGHV1-2, 24.9%; IGHV4-34, 12.8%; IGHV3-23: 8.1%, respectively), significantly extending previous similar observations. Particularly for the IGHV1-2 gene, strong biases became evident at the level of utilization of different alleles, since 79/86 rearrangements (92%) utilized allele *04 vs. only 7/86 rearrangements (8%) that utilized allele *02. This is noteworthy, taking into consideration that these two alleles differ in a single nucleotide, leading to a single amino acid change in framework region (FR)-3. The repertoire biases became more pronounced when the analysis was focused on 171 rearrangements from 163 cases classified as SMZL based on splenic histopathology, according to the 2008 WHO criteria. Within this subgroup, 56/171 cases (32.7%) utilized IGHV1-2*04. Noticeably, only 1/17 cases with a diagnosis of splenic diffuse red pulp lymphoma utilized IGHV1-2*04 (p<0.02 for comparison to SMZL). The IGHV1-2*04 rearrangements carried significantly longer heavy complementarity-determining region-3 (VH CDR3) than all other cases (median, 22 vs. 17 amino acids, respectively; p<0.001). In addition, 52/79 IGHV1-2*04 cases (65.8%) employed one of the IGHD3-3, IGHD3-9 or IGHD3-10 genes. In 28/32 IGHV1-2*04/IGHD3 rearrangements, the IGHD gene was utilized in the same reading frame, leading to VH CDR3s with common “IGHD-derived” amino acid (AA) motifs. Using bioinformatics tools previously applied to CLL, biased associations of IGHV, IGHD and IGHJ genes with stereotyped VH CDR3s were identified in 25/345 sequences (7.2%). Noticeably, only 10/28 IGHV1-2*04/IGHD3-3 rearrangements with “IGHD-derived” VH CDR3 amino acid motifs could be assigned to “stereotyped” clusters. Despite exhibiting restricted usage of the IGHV1-2*04 and IGHD3-3 genes leading to great overall VH domain similarity, the remaining cases did not fulfill the established criteria for VH CDR3 “stereotypy”, as defined in other lymphoid malignancies, namely CLL. Based on somatic hypermutation (SHM) analysis, the sequences were divided into three groups: (i) truly unmutated (100% germline identity, GI): 46/345 sequences (13.3%); (ii) minimally/borderline mutated (97-99.9% GI): 130/345 sequences (37.7%); and (iii) significantly mutated (<97% identity): 169/345 sequences (49%). At the individual gene level, the distribution of rearrangements of IGHV genes according to SHM status varied significantly. In particular, 56/79 IGHV1-2*04 rearrangements (71%) were predominantly “borderline mutated”, whereas the majority (>67%) of rearrangements utilizing the IGHV3-23, IGHV3-30 and IGHV3-7 genes were “significantly mutated”; finally, IGHV4-34 gene rearrangements were evenly distributed to the three mutational subgroups. Shared (“stereotyped”) AA changes were identified for IGHV1-2*04 rearrangements, with certain FR2 and FR3 codons emerging as “hotspots” for recurrent, conservative AA changes. In conclusion, we demonstrate that more than 30% of cases with a histopathological diagnosis of SMZL on the spleen express IGHV1-2*04 receptors with unusually long VH CDR3s, biased usage of the IGHD3-3 gene, leading to shared “IGHD-derived” VH CDR3 motifs, and very precise molecular features of SHM. The biased expression of a distinctive germline-encoded VH specificity might be considered as evidence for heavy chain dominance in the clonogenic IG receptors in SMZL. These findings allude to selection by specific (super)antigenic element(s) in the pathogenesis of at least a major subset of SMZL. In addition, they raise the intriguing possibility that certain subtypes of SMZL could derive from progenitor cell populations adapted to particular antigenic challenges through cellular selection of VH domain specificities. Disclosures: No relevant conflicts of interest to declare.

Stratification Approach for Splenic Marginal Zone Lymphoma Based on Hemoglobin, Platelet Count, High LDH and Extrahilar Lymphadenopathy: The HPLL/ABC System

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1583-1583 ◽  
Author(s):  
Carlos Montalban ◽  
Victor Abraira ◽  
Luca Arcaini ◽  
Eva Domingo-Domenech ◽  
Pablo Guisado-Vasco ◽  
...  
Keyword(s):  
Cancer Research ◽  
Platelet Count ◽  
Research Funding ◽  
Marginal Zone ◽  
Risk Groups ◽  
Marginal Zone Lymphoma ◽  
Splenic Marginal Zone Lymphoma ◽  
Training Set ◽  
Conditioning Treatment ◽  
Significant Difference

Abstract Abstract 1583 Splenic Marginal Zone Lymphoma (SMZL) is a distinct lymphoma included in the WHO 2008 classification. Ann Arbor staging system is not adequate to stratify SMZL patients into risk groups, as blood and bone marrow are usually involved. Further, there are neither established criteria for starting treatment nor gold standard treatment. Herein we report an international retrospective study on 593 SMZL patients aimed to identify which factors could influence starting treatment and which could allow stratify risk categories. Logistic regression was used to identify the factors that have conditioned treatment in the whole series and Cox regression for factors influencing Lymphoma Specific Survival (LSS) in a training set of 336 patients. The variables used were age, hemoglobin level and platelet count (as continuous variables) and sex, low albumin serum level (<3 gr/dl), high LDH and β2microglobulin, serum monoclonal component, DAT positivity, active autoimmune anemia, HCV positivity, lymphadenopathy (other than in hepatic and splenic hila) and extranodal involvement. The final model for LSS was used to produce a prognostic index (PI) and allowed to divide the patients in three risk groups applying cutpoints at the 20th and 80th centiles in patients with events. The resulting stratification was validated in another set of 227 patients. Also, the stratification was compared with the Interguppo Italiano Linfomi (IIL) score in the set of 450 patients in whom the required data were available, using the extension net reclassification improvement (NRI). Hemoglobin (p=0.000), extrahilar lymphadenopathy (p=0.000), and HCV positivity (p=0.001), were the factors independently conditioning treatment. Untreated patients had a significant longer LSS than treated patients (p=0.000). In the treated group there were no differences in LSS according to the type of therapy (splenectomy, chemotherapy, rituximab or their combinations) (Figure A). The low number of rituximab treated patients (n=39) precluded statistically reliable conclusions. In the training set, haemoglobin (p=0.003), platelet count (p=0.043), high LDH (p=0.011) and extrahilar lymphadenopathy (p=0.020) were the factors independently influencing LSS. The resulting PI was: 0.6 × platelet count (in hundreds of thousands/mm3) + 0.2 × hemoglobin (g/dl) − 1 × high LDH (1 when LDH above normal, 0 when normal) – 0.75 × extrahilar lymphadenopathy (1 when present, 0 when absent). Applying the cut points a low, intermediate and high risk groups with significantly different 5 year LSS of 0.94, 0.78 and 0.67, respectively, were identified (Figure B). In the validation set the system also separated 3 groups with significant different 5 year LSS of 0.96, 0.88 and 0.44, respectively. This stratification was named HPLL after the determinant factors (H emoglobin, P latelet count, high L DH, L ymphadenopathy) and the resulting risk groups HPLLA, HPLLB and HPLLC. In the comparison HPLL/ABC system separated 3 groups with significantly different LSS, whereas in the IIL score there was no significant difference between the low and intermediate risk groups (p=0,102). Using as reclassification calibration statistics the Hosmer-Lemeshow test, HPLL/ABC (χ2 =1.48; p=0.475) showed a better fit than the IIL score (χ2= 3.339; p=0.118) indicating that HPLL/ABC discriminated better the risk groups. In this large SMZL series, haemoglobin, extrahilar lymphadenopathy and HCV positivity were the factors independently conditioning treatment. The combination of hemoglobin, platelet count, high LDH and extrahilar lymphadenopathy stratify the patients in three groups with significantly different outcome. This system may be helpful to select risk-tailored treatment approaches. Disclosures: Montalban: Red Temática de Investigación Cooperativa en Cancer (RETICC): Research Funding; Asociación Española contra el Cancer: Research Funding. Mollejo:Red Temática de Investigación Cooperativa en Cancer (RETICC): Research Funding; Asociación Española contra el Cancer: Research Funding. Piris:Red Temática de Investigación Cooperativa en Cancer (RETICC): Research Funding; Asociación Española contra el Cancer: Research Funding.

Outcomes In Splenic Marginal Zone Lymphoma: Analysis Of 108 Patients Treated In British Columbia (BC)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4369-4369
Author(s):  
Katharine He Xing ◽  
Amrit Kahlon ◽  
Joseph M. Connors ◽  
Brian Skinnider ◽  
Randy D. Gascoyne ◽  
...  
Keyword(s):  
British Columbia ◽  
Hepatitis C ◽  
Research Funding ◽  
Marginal Zone ◽  
B Cell Lymphoma ◽  
Marginal Zone Lymphoma ◽  
Transformation Rate ◽  
Splenic Marginal Zone Lymphoma ◽  
First Line

Abstract Introduction Splenic marginal zone lymphoma (SMZL) is uncommon and accounts for less than 1% of all non-Hodgkin lymphomas. The optimal treatment for SMZL is unknown. We describe the outcome of 108 patients with SMZL treated in British Columbia. Methods All patients with SMZL diagnosed between 1985 and June 2012 were identified in the BC Cancer Agency Centre for Lymphoid Cancer and Lymphoma Pathology Databases. Overall survival (OS) was measured from time of diagnosis to death or last follow-up. Progression-free survival (PFS) was measured from the date of diagnosis to the date of lymphoma recurrence or transformation, or death. Time to transformation (TTT) was calculated from date of diagnosis to date of transformation to aggressive lymphoma. Results 108 patients were identified with a diagnosis of SMZL. Baseline patient characteristics: median age 67 years (range 30-88), male 41%, stage IV 98%, B symptoms 17%, performance status ≥2 22%, splenomegaly 93%, bone marrow involvement 93%, peripheral blood involvement 87%. Hepatitis C serology was positive in 5 of 60 patients with available data. As initial treatment, 53 underwent splenectomy (10 with chemotherapy), 38 chemotherapy alone (21 with a rituximab-containing regimen), 2 received antiviral therapy for hepatitis C, and 15 were observed. Of the 43 patients who had splenectomy alone, 9 subsequently received chemotherapy upon progression, 1 had excision for a soft tissue mass, and 4 transformed to diffuse large B cell lymphoma (DLBCL). Of the 38 who received chemotherapy first line, 6 subsequently received combined chemotherapy and splenectomy, 1 splenectomy alone, 4 chemotherapy alone, and 7 transformed to DLBCL. Neither of the 2 patients who received antivirals had further progression. With a median follow-up of 7 years (range 3 months to 18 years) for living patients, the 5 and 10 year OS were 65% and 48%, respectively. The 5 and 10 year PFS were 38% and 18%, respectively. The 5 year OS for patients who had a splenectomy as their first-line therapy compared to other treatments was 76% vs 53% (p=0.01); and the 5 year OS for patients who received chemotherapy alone as first-line compared to other treatments was 52% vs 72% (p=0.04). There was no difference in outcomes between those treated with rituximab containing chemotherapy as first line compared to other treatments (p=0.65). The 5 and 10 year PFS after first-line splenectomy were 52% and 18%, respectively. A total of 14 patients transformed to DLBCL with a median TTT of 3.2 years (range 6 months to 11.9 years). The 5, 10, 15 year rates of transformation were 9%, 21% and 35%, respectively. Conclusions Splenectomy remains a reasonable treatment option for patients with SMZL. Patients selected for splenectomy as initial management of symptomatic disease experience improved outcomes. The transformation rate in SMZL is similar to that of other indolent lymphomas. Disclosures: Connors: F Hoffmann-La Roche: Research Funding; Roche Canada: Research Funding. Skinnider:Roche Canada: Research Funding. Gascoyne:Roche Canada: Research Funding. Sehn:Roche Canada: Research Funding. Savage:Roche Canada: Research Funding. Slack:Roche Canada: Research Funding. Shenkier:Roche Canada: Research Funding. Klasa:Roche Canada: Research Funding. Gerrie:Roche Canada: Research Funding. Villa:Roche Canada: Research Funding.

Survival with splenectomy in splenic marginal zone lymphoma: Analysis of the Surveillance, Epidemiology and End Results (SEER) database.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8044-8044
Author(s):  
Adam J. Olszewski
Keyword(s):  
Propensity Score ◽  
Survival Data ◽  
Marginal Zone ◽  
Relative Survival ◽  
Marginal Zone Lymphoma ◽  
Splenic Marginal Zone Lymphoma ◽  
Primary Therapy ◽  
Seer Database ◽  
The Impact

8044 Background: The role of splenectomy as the primary therapy for splenic marginal zone lymphoma has been questioned. We studied relative survival in SMZL and the impact of splenectomy on lymphoma-specific survival (LSS). Methods: SMZL cases (diagnosed in 1993-2008) were derived from the SEER database. Age, sex and race-matched actuarial survival data were summarized. Factors predictive of splenectomy were studied using logistic regression with a subsequent propensity score (PS)-weighted survival analysis. Results: 1071 patients were identified with a median age of 69 years (range, 25-96) and a median follow up of 33 months. 53% were women and 92% were white. 70% of the lymphomas were stage III/IV with B symptoms recorded in 22.3%. 54% of patients underwent splenectomy. The significant factors predictive of surgery included younger age (p<10-14), stage I/II (p<10-15), B-symptoms (p=0.003), no prior malignancy (p=0.002), with significantly lower rates in black patients (OR 0.41, 95%CI 0.21-0.80, p=0.008), on the Pacific Coast (OR 0.62, 95%CI 0.47-0.81, p=0.0004) and with decreasing rates over time (p=0.0002). The actuarial 5-year relative survival was 82.8% (95%CI 77.9-86.7%) with no difference by sex (p=0.79), race or stage. 54% of deaths were related to SMZL with the estimated LSS of 80.8% (95%CI 78-84%). Splenectomy was not associated with improved LSS in propensity score-stratified log-rank test (p=0.60) or in the PS-weighted Cox model (HR=0.93, 95%CI 0.62-1.38, p=0.70). Advancing age (HR 1.05, 95%CI 1.03-1.07, p<10-8) and presence of B-symptoms (HR=1.98, 95%CI 1.30-3.01, p=0.002) were significantly predictive of death from SMZL, with no evidence of improvement in LSS over the years (HR=0.97, 95%CI=0.91-1.03, p=0.34). There was also no detectable impact of splenectomy on survival in patients who ultimately died of SMZL (p=0.83). Conclusions: In this cohort, the largest studied to date, splenectomy did not demonstrate a survival benefit in SMZL. Patients continue to have decreased survival despite advances in other indolent B-cell lymphomas. The role of splenectomy versus chemoimmunotherapy remains to be determined.

scholarly journals Deep-Sequencing Reveals the Molecular Landscape of Splenic Marginal Zone Lymphoma: Biological and Clinical Implications

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 76-76
Author(s):  
Matthew JJ Rose-Zerilli ◽  
Marina Parry ◽  
Viktor Ljungstrom ◽  
Jane Gibson ◽  
Jun Wang ◽  
...  
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Sanger Sequencing ◽  
Marginal Zone ◽  
Gene Mutations ◽  
Marginal Zone Lymphoma ◽  
Similar Proportion ◽  
Cell Physiology ◽  
Splenic Marginal Zone Lymphoma ◽  
B Cell Malignancies

Abstract Whilst the spectrum and clinical significance of gene mutations and immunogenetic features in common mature B-cell malignancies is well established, their incidence, biological and clinical importance in splenic marginal zone lymphoma (SMZL) remains uncertain. Accordingly we screened 175 well-characterised SMZL cases for mutations in 768 genes (Haloplex Target Enrichment System) with a known or postulated role in B-cell physiology, B-cell malignancies in general and SMZL pathophysiology in particular. After sequencing (HiSeq 2000) we achieved a mean depth across our gene panel of 297-fold (range 128-702x), with more than 85% of all bases covered at >50-fold. After comprehensive filtering, 1,374 single nucleotide variants and insertions/deletions were identified. 221 genes were recurrently mutated at a gene frequency of 2-16% [n=2-28]. Sanger sequencing confirmed 86/86 selected variants in our recurrent genes, and showed 99% concordance between our Haloplex and Sanger sequencing of NOTCH2 exon 34, which was performed in all patients. Comprehensive validation of both germ-line Haloplex [n=18 patients] and Sanger sequencing established the sensitivity and specificity of our approach, and confirmed the biological importance and somatic origin of the genes described herein. To identify biologically relevant genes, we employed MutSigCV analysis, an algorithm that identifies significantly mutated genes by accounting for background mutation rate, DNA replication time and the gene size. 18 mutated genes were identified with TP53 [n=28], KLF2 [n=21], MYD88 [n=12], NOTCH2 [n=17], TNFAIP3 [n=13] and CCND3 [n=15] being the most significant; genes that encode components of pathways important in the regulation and differentiation of mature B-cells were also identified, including CREBBP [n=9], MAP3K6 [n=5], KDM2B [n=7], SETD1B [n=6], TRAF3 [n=9], ARID1A [n=10], BIRC3 [n=3], BCL10 [n=5], BTG1 [n=3], ATM [n=10], NFKBIE [n=4] and DDI1 [n=4]. Then, we searched for significant pairwise gene correlations and mutually exclusive relationships between our mutated genes demonstrating the following: (1) independent events, such as MYD88, where a mutation is invariably observed as an isolated event; (2) cancer drivers that have a similar proportion of co-occurring and mutually-exclusive relationships, such as NOTCH2, TP53, TNFAIP3 and CREBBP, and (3) genes such as KLF2, CCND3 and ARID1A that have proportionally more co-occurring relationships, thus suggesting a synergistic function to promote tumorigenesis. Finally, we studied clonal evolution, by differentiating between early, clonal events, and later, subclonal mutations (ABSOLUTE algorithm), and we were able to classify clonal or subclonal mutation in 6/18 of our MutSigCV genes. Paradigmatically, we observed that all the CREBBPmutations were fully clonal. Amongst our most novel findings was KLF2, or Krüppel-like factor 2, mutations that were distributed across the entire protein, with a cluster in the C2H2 domain and were all somatically acquired. All mutations tested were clonal, significantly associated with del(7q) (P=0.001), IGHV1-2*04 gene usage (P<0.001) and other gene mutations including NOTCH2 (all P<0.001). Together, these observations suggest that the potential cell survival advantage provided by an early KLF2 mutation allows the acquisition of additional functionally synergistic gene mutations to promote tumourigenesis. Genes associated with reduced time to first treatment (TTFT) included KLF2 (HR 1.93, 95%CI 1.16-3.32, p=0.01), and NOTCH2 (HR 2.13, 95%CI1.26-3.58, p=0.003). TP53 mutations were associated with shorter event-free (EFS) and overall survival (OS) (HR 2.17, 95%CI 1-4.74, p=0.05 and HR 2.16, 95%CI 1.05-4.42, p=0.032, respectively). Using multivariate Cox proportional hazard analysis, which included base-line clinical varaibles, both NOTCH2 (HR 2.12, 95%CI 1.02-4.4, p=0.044) and 100% germline IGHV gene identify (HR 2.19, 95%CI 1.05-4.55, p=0.036) were independent risk factors for TTFT. Furthermore, the presence of TP53 mutation was an independent risk factor for OS (HR 2.16, 95%CI 1.05-4.43, p=0.032). In summary, we have defined the mutational landscape in a large cohort of patients with SMZL and identified novel recurrent mutations, especially involving KLF2. Importantly we show for the first time, that gene mutations and immunogenetic features have independant prognostic significance. Disclosures Anagnostopoulos: Gilead Sciences: Research Funding. Fazi:Rhizen Pharmaceuticals SA: Research Funding. Ghia:Merck: Consultancy; GSK, Roche Italia: Consultancy; Gilead, Pharmacyclics, Boehringer Ingelheim, Celgene, Roche Italia: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Decreased Lymphoma-Specific Mortality in Patients with Splenic Marginal Zone Lymphoma in the United States

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 9-9
Author(s):  
John L Vaughn ◽  
Laura C Pinheiro ◽  
Adam J Olszewski ◽  
Narendranath Epperla
Keyword(s):  
Competing Risks ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Marginal Zone ◽  
Marginal Zone Lymphoma ◽  
Splenic Marginal Zone Lymphoma ◽  
Advanced Stage ◽  
Stage At Diagnosis ◽  
The Past ◽  
Specific Mortality

Introduction: Splenic marginal zone lymphoma (SMZL) is an indolent B-cell non-Hodgkin lymphoma that usually presents in elderly patients with splenomegaly, lymphocytosis, and cytopenias (either due to hypersplenism or autoimmune phenomena). Treatment of SMZL has advanced over the past decade including identification of better tolerable chemotherapy regimens (such as rituximab and bendamustine) and the advent of novel agents (such as ibrutinib and lenalidomide). We sought to determine whether advances in treatment and supportive care over the past decade have translated to decreased lymphoma-specific mortality among patients with SMZL. Method: We used the population-based Surveillance, Epidemiology, and End Results (SEER)-18 database. We included adult patients with SMZL diagnosed between 2000-2017 who were 18-84 years old at the time of diagnosis. We excluded patients with a history of malignancy prior to SMZL, those with missing survival times and those with central nervous system involvement. Patients were divided into two cohorts based on period of diagnosis (era-1: 2000-2008, and era-2: 2009-2017). Five-year relative survival (RS) was estimated using the Pohar-Perme method. Differences between RS distributions was tested with a log-rank-type test. The risk of SMZL-specific death was estimated by calculating the cumulative incidence function (CIF). The difference between CIF distributions was tested with the Pepe-Mori test. The competing risks of SMZL-specific death and death from other causes were modeled using Fine and Gray regression. All tests of differences were performed at a two-sided alpha of 0.05. Results: We included 1,548 patients with SMZL. Table 1 shows the baseline characteristics. The median age at diagnosis was 66 years (IQR = 57-74) years. Most patients were non-Hispanic White (81%) with advanced stage at diagnosis (stage III-IV, 70%). Five-year RS was 84% (95% CI = 80-87%) during era-1 and 89% (95% CI = 85-92%) during era-2 (p = 0.21. The CIF distributions for SMZL-specific death and death from other causes are shown in Figure 1A and Figure 1B, respectively (Pepe-Mori p = 0.02). In our multivariable competing risks model, the period of diagnosis, age, and stage at diagnosis were significant predictors of SMZL-specific death (Table 2). Patients in era-2 had significantly lower risk of SMZL-specific death [subhazard ratio (SHR) = 0.30, 95% CI = 0.22-0.41), while the cumulative incidence of mortality significantly increased with age (SHR = 1.39 per decade, 95% CI = 1.24-1.56) and advanced stage (SHR = 1.55, 95% CI= 1.04-2.13). Conclusion: There has been a significant reduction in the risk of SMZL-specific death for patients with SMZL in the most recent era possibly due to advances in therapy. This reduction in mortality persists even after accounting for competing risks of mortality from other causes. Disclosures Olszewski: Spectrum Pharmaceuticals: Research Funding; Adaptive Biotechnologies: Research Funding; TG Therapeutics: Research Funding; Genentech, Inc.: Research Funding. Epperla:Verastem Oncology: Speakers Bureau; Pharmacyclics: Honoraria.

Ongoing Antigen Interactions In Splenic Marginal Zone Lymphoma: Revelations From The Analysis Of Intraclonal Diversification In Immunoglobulin Light Chain Genes

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2999-2999
Author(s):  
Maria Karypidou ◽  
Evangelia Stalika ◽  
Panagiotis Baliakas ◽  
Vasilis Bikos ◽  
Zadie Davis ◽  
...  
Keyword(s):  
Marginal Zone ◽  
Conflicts Of Interest ◽  
Marginal Zone Lymphoma ◽  
Molecular Evidence ◽  
Splenic Marginal Zone Lymphoma ◽  
Gene Repertoire ◽  
Nucleotide Substitutions ◽  
Time Points ◽  
Molecular Features ◽  
Mutational Status

Abstract Immunogenetic studies have made seminal contributions towards understanding the pathogenesis of splenic marginal zone lymphoma (SMZL) by documenting a highly skewed immunoglobulin (IG) gene repertoire with molecular features strongly implicating selection by antigen(s) in disease ontogeny and evolution. Indeed, a major subset of SMZL, roughly 30% of the entire cohort, is defined by the expression of IG receptors with heavy variable domains (VH) utilizing the IGHV1-2*04 gene. These VH domains exhibit low-level, yet non-randomly targeted somatic hypermutation (SHM), carry long and often positively charged heavy complementarity-determining region 3 with restricted motifs, and also show biased associations with certain light IG genes, namely IGKV3-20, IGKV1-8 and IGLV2-14. We recently documented that the great majority of SMZL, especially IGHV1-2*04 cases, exhibit intraclonal diversification (ID) in IGHV genes, reflecting ongoing interactions with antigen(s). In this study we further extend the analysis of ID in SMZL focusing on IG light genes. To this end, we performed a comprehensive subcloning analysis of IGKV-IGKJ and IGLV-IGLJ gene rearrangements from 11 SMZL cases; two patients were studied at two different time-points. A total of 311 subcloned sequences (10-38/sample, median, 25) were obtained from 9 IGKV-IGKJ and 4 IGLV-IGLJ rearrangements. Multiple alignment of the subcloned sequences revealed that: (1) only one of 13 studied samples (7.8%) carried identical subclones (no ID); (2) 6/13 (46.1%) carried only unconfirmed mutations (UCMs, mutations in single subclones; unconfirmed ID); and, (3) 6/13 (46.1%) carried confirmed mutations (CMs, identical mutations in at least 2 subclones; confirmed ID). Both IGHV1-2*04 cases of the present series belonged to the confirmed ID category and both displayed intense ID with extensive subclone formation. Among cases positive for ID, the number of nucleotide substitutions introduced by ongoing SHM ranged from 1-21. A total of 66 unique substitutions were identified in 42 positions of the variable domain; 44 of these resulted in the replacement of the germline-encoded amino acid (R), while the remaining 22 were silent (S). The distribution of replacement and silent CMs and UCMs in CDRs and FRs was compatible with a canonical SHM process in that R/S ratios were higher in CDRs, except CDR2. In general, ID was more pronounced in IGKV-IGKJ versus IGLV-IGLJ rearrangements, regardless of the overall mutational load of each rearrangement. The analysis of the same rearrangement at different time-points revealed a consistent ID profile: one case carried only UCMs at both time-points, while the other (IGHV1-2*04 case) exhibited a dynamic pattern of appearing and disappearing CMs. Overall, the presence of mutations in the context of ID was independent of the mutational status, as ID was observed even in minimally mutated cases (98-99.9% germline identity). Moreover, in 3/6 cases with confirmed ID, subclones were classified in ≥2 main mutational groups, indicating early “branching” of the clonal population in subpopulations with distinct mutational profiles. In conclusion, the present study complements the immunogenetic profile of SMZL, offering novel molecular evidence for crosstalk with the microenvironment mediated through the clonotypic B-cell receptors. Furthermore, it underscores the significance of IG light chains in the immune pathogenesis of SMZL. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Clinical features and possible prognostic factors in patients with Marginal Zone Lymphoma: Retrospective analysis from two centers

2021 ◽  
Author(s):  
Pınar Akyol ◽  
Abdulkerim Yıldız ◽  
Murat Albayrak ◽  
Murat Yıldırım ◽  
Mesut Tığlıoğlu ◽  
...  
Keyword(s):  
Overall Survival ◽  
Platelet Count ◽  
Marginal Zone ◽  
Marginal Zone Lymphoma ◽  
Splenic Marginal Zone Lymphoma ◽  
Need For Treatment ◽  
Significant Difference ◽  
Hematological And Biochemical Parameters ◽  
Nodal Marginal Zone Lymphoma ◽  
The Impact

Abstract Objectives Marginal zone lymphoma accounts 5%-17% of all non-Hodgkin lymphomas and has an indolent clinical course. The parameters that predict prognosis and the need for treatment are still unclear. The aim of the current study was to examine the impact of parameters on the course of disease and the need for treatment in marginal zone lymphoma. Methods A retrospective study was conducted with marginal zone lymphoma patients in the two centres between 2010 and 2018. The demographic and disease characteristics, and also hematological and biochemical parameters at the time of diagnosis were examined. The effect of the parameters on overall survival and need for treatment were analyzed. Results During the follow-up, 25 patients required treatment and 15 patiens were followed up without treatment. Overall survival was significantly higher in patients with nodal marginal zone lymphoma than in extranodal and splenic marginal zone lymphoma patients. overall survival of patients who required treatment was 92.9 months while untreated patients was 58.4 months and there was no significant difference among the groups. The platelet count of untreated patients at the time of diagnosis were significantly higher than patients who received treatment. No significant relationship was found between any parameter and overall survival. Conclusions We demonstrated platelet count at the time of diagnosis as a predictive factor for future treatment need. It is an objective and simple blood test that may be helpful to predict the course of the disease although further studies are warranted.

scholarly journals Splenic Marginal Zone Lymphoma: Risk of Transformation, Clinico-Biological Features at Transformation and Prognosis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4015-4015
Author(s):  
Gabriela Bastidas ◽  
Silvia Bea ◽  
Alba Navarro ◽  
Eva Gine ◽  
Julio Delgado ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Research Funding ◽  
Marginal Zone ◽  
B Cell Lymphoma ◽  
Marginal Zone Lymphoma ◽  
Splenic Marginal Zone Lymphoma ◽  
Complex Karyotype ◽  
Biological Features ◽  
Histological Transformation

BACKGROUND: The clinical course of splenic marginal zone lymphoma (SMZL) is usually indolent, but development of transformation to aggressive lymphoma (SMZL-T) is seen in 10 to 15% of the cases. Risk factors to predict SMZL-T are poorly defined. AIM: The aims of our study were: 1.- to assess the risk of transformation in a large series of SMZL patients; 2.- to analyze the prognostic factors for this event and 3.- to analyze clinical and biological features of SMZL-T. PATIENT AND METHODS: We identified 84 SMZL diagnosed at the HCB between 1994 and 2017 and 15 of them (18%) had developed histological transformation (SMZL-T). In addition, we reviewed 21 SMZL with transformation referred to HCB from other centers. Median age at diagnosis of low-grade SMZL in the 84 patients was 63 years (range, 32-91), and male/female ratio was 34/50. Complex karyotype (CK) defined as ≥3 chromosomal aberrations by conventional cytogenetics was observed in 22% and del(7q) in 59% of cases. The risk distribution according to the Splenic Marginal Zone Lymphoma Study Group simplified score HPLL/ABC was: low: 34, intermediate: 51 and high: 15. After a median follow-up of 80 months (range, 1-265), 37 of 84 (44%) patients have died, with a median overall survival (OS) of 146 months. To assess the risk of transformation and to identify predictive factors for such event, we exclusively evaluated the cohort of 84 patients from HCB. RESULTS: Fifteen of the 84 patients in the HCB cohort (18%) developed histological transformation. The cumulative incidence of transformation at 60 months from diagnosis was 15% (95% CI: 7 - 23) (Figure). In univariate analysis, variables predicting transformation were anemia, lymphopenia, thrombocytopenia, hypoalbuminemia, CK and high-risk scores of Intergruppo Italiano Linfomi (IIL) and HPLL (p<0.05 for all variables). In addition, lack of response to front-line treatment, relapse, and an early relapse at 12 and 24 months from treatment (p<0.05 for all variables) predicted for a higher risk of transformation. In multivariate analysis, only CK maintained significance to predict transformation (HR 4.85 (CI 95%: 1.15-20.56) p=0.03). Main clinico-biological features of all 36 SMZL-T patients (including HCB patients and those referred from other centers) are described in the Table. Thirty-five patients transformed to diffuse large B-cell lymphoma (DLCBL) and 1 to Hodgkin lymphoma. Treatment at transformation is detailed in Table. Response was assessable in 34 cases: 21 (62%) achieved a complete response (CR), and 13 patients did not respond. Among responders, 11 continue in CR, 9 relapsed during the follow-up and 1 patient died from therapy related acute myeloid leukemia (AML) when still in CR. Twenty SMZL-T patients (56%) eventually died, 19 related to lymphoma and 1 from AML. The median survival of the 36 SMZL-T patients from the time of transformation (SFT) was 59 months; with 60-months SFT of 46% (95% CI: 28-64) (Figure). Variables at the time of transformation predicting survival were age >60 years, thrombocytopenia and renal impairment. In addition, patients not achieving a CR, those not receiving an ASCT, and those who relapsed had a poorer SFT (p<0.05 for all variables). In multivariate analysis the independent variables predicting a worse SFT were: age > 60 years (HR 6.28 (95% CI: 1.55-25.39), p=0.01), thrombocytopenia (HR 32.77 (95% CI: 1.97-546.06), p=0.01), and response < CR (HR 8.75 (95% CI: 2.76-27.72), p<0.0001). Finally, SMZL-T was analyzed as a time-dependent variable for OS, showing that patients who eventually developed transformation had a significant higher risk of death (HR 3.894 (95% IC: 1.816-8.350), p<0.001). CONCLUSION: The risk of SMZL-T in our series of HCB was 15% at 60 months. The only factor that significatively predicted risk of SMZL-T in a multivariant analysis was the presence of complex karyotype. SMZL-T patients had a significative shorter survival compared to not transformed patients. Disclosures Gine: Roche: Other: Travel expenses, Research Funding; Gilead: Other: Travel expenses, Research Funding; Janssen: Other: Travel expenses, Research Funding. Lopez-Guillermo:Celgene: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Janssen: Research Funding.

Sign in / Sign up

Export Citation Format

Share Document